The large family of PC4-like domains – similar folds and functions throughout all kingdoms of life

Abstract

RNA-and DNA-binding domains are essential building blocks for specific regulation of gene expression. While a number of canonical nucleic acid binding domains share sequence and structural conservation, others are less obviously linked by evolutionary traits. In this review, we describe a protein fold of about 150 aa in length, bearing a conserved β-β-β-β-α-linker-β-β-β-β-α topology and similar nucleic acid binding properties but no apparent sequence conservation. The same overall fold can also be achieved by dimerization of two proteins, each bearing a β-β-β-β-α topology. These proteins include but are not limited to the transcription factors PC4 and P24 from humans and plants, respectively, the human RNA-transport factor Pur-α (also termed PURA), as well as the ssDNA-binding SP_0782 protein from Streptococcus pneumonia and the bacteriophage coat proteins PP7 and MS2. Besides their common overall topology, these proteins share common nucleic acids binding surfaces and thus functional similarity. We conclude that these PC4-like domains include proteins from all kingdoms of life and are much more abundant than previously known.

The novel anti-CRISPR AcrIIA22 relieves DNA torsion in target plasmids and impairs SpyCas9 activity

“…Structural evidence supported the same conclusion, as AcrIIA22 was predicted to form a stable tetramer when analyzed with PISA, a tool for inferring macromolecular assembles from crystalline structure 25 (Figures 4D, 4E). This putative tetramer has a molecular mass consistent with that observed by SEC and comprises pairs of outward-facing, concave β-sheets, as is seen in other PC4-like proteins 24 . Interestingly, many PC4-like proteins bind nucleic acids using similar concave β-sheets and, in some instances, form higher-order oligomers as a necessary step for binding DNA or RNA 24 .…”

“…This putative tetramer has a molecular mass consistent with that observed by SEC and comprises pairs of outward-facing, concave β-sheets, as is seen in other PC4-like proteins 24 . Interestingly, many PC4-like proteins bind nucleic acids using similar concave β-sheets and, in some instances, form higher-order oligomers as a necessary step for binding DNA or RNA 24 . Consistent with this possibility, adjacent β-sheets along each outward face of the putative AcrIIA22 tetramer form a groove that could potentially accommodate a nucleic acid substrate (Figure 4E).…”

“…This prediction, together with our inference from genomic analyses (Figure 2), led us to hypothesize that AcrIIA22 may have similar recombination-stimulating activity. Indeed, other PC4-like proteins have been observed experimentally to unwind duplex DNA, a function consistent with their proposed roles in transcription and recombination 24,28 . Therefore, we investigated whether AcrIIA22 might interact with duplexed DNA in a manner consistent with its putative recombinogenic properties.…”

“…A DALI structure-structure search revealed that the AcrIIA22 monomer is similar to members of the newly recognized PC4-like structural fold (Figure 4B, Supplemental Table 2). PC4-like proteins have independently evolved in all domains of life, typically adopt a β-β-β-β-α topology, and often homodimerize to bind diverse RNA and DNA species using variably positioned β-sheets 24 .…”

The Molecular Function of PURA and Its Implications in Neurological Diseases

“…With a conserved β-β-β-β- α topology, each of the two PUR repeats folded into a four-stranded beta sheet, followed by a single alpha helix. Such a PUR domain can either be built from a single peptide chain with a β-β-β-β-α-linker- β-β-β-β-α topology (type I) or from two identical peptides with β-β-β-β-α fold, forming an inter-molecular homodimer (type II; Figures 1B , C ; Janowski and Niessing, 2020 ). In both cases, the α-helices swap between both β-β-β-β-α repeats.…”